WO2014098063A1 - 軸不斉を有するN-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物及びそれを使用するα-アミノ酸のキラリティ変換方法 - Google Patents
軸不斉を有するN-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物及びそれを使用するα-アミノ酸のキラリティ変換方法 Download PDFInfo
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- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000001925 cycloalkenes Chemical group 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- HKIOYBQGHSTUDB-UHFFFAOYSA-N folpet Chemical group C1=CC=C2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2=C1 HKIOYBQGHSTUDB-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 229940031993 lithium benzoate Drugs 0.000 description 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N lithium oxide Chemical compound [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- LDJNSLOKTFFLSL-UHFFFAOYSA-M lithium;benzoate Chemical compound [Li+].[O-]C(=O)C1=CC=CC=C1 LDJNSLOKTFFLSL-UHFFFAOYSA-M 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- BQPIGGFYSBELGY-UHFFFAOYSA-N mercury(2+) Chemical compound [Hg+2] BQPIGGFYSBELGY-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- HZQDHBGMMKYQDP-UHFFFAOYSA-N n-(2-benzoylphenyl)-2-bromoacetamide Chemical compound BrCC(=O)NC1=CC=CC=C1C(=O)C1=CC=CC=C1 HZQDHBGMMKYQDP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/04—Nickel compounds
- C07F15/045—Nickel compounds without a metal-carbon linkage
Definitions
- the present invention uses N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compounds having axial asymmetry and the template as a template
- the present invention relates to a chirality conversion method for ⁇ -amino acids.
- the present invention also provides an ⁇ -amino acid condensate of N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compound used as an intermediate. It also relates to a metal complex as a ligand.
- Optically pure ⁇ -amino acids are useful as building blocks in designing, for example, various physiologically active substances and pharmaceuticals.
- a substance incorporating a D- ⁇ -amino acid that hardly exists in nature has a specific physiological action, and a method for easily obtaining an optically pure D- ⁇ -amino acid as a raw material Development is desired.
- optically active non-natural artificial ⁇ -amino acids are becoming increasingly important in drug development due to the effect of stabilizing the higher-order structure of peptides and proteins and the stability to hydrolases. Development of a simple method for obtaining the optically active substance is also an urgent issue.
- N- (2-acylaryl) -2- [5,7-dihydro-6H- which can be used as a template in converting the chirality of an ⁇ -amino acid.
- a dibenzo [c, e] azepin-6-yl] acetamide compound was successfully created.
- This S- or R-form acetamide compound is appropriately selected, condensed with an ⁇ -amino acid to be converted to chirality, then converted into a metal complex, and heated under basic conditions to convert the chirality of the ⁇ -amino acid moiety,
- a method for obtaining an ⁇ -amino acid having a desired chirality in a high yield and high enantioselectivity by releasing the ⁇ -amino acid again by the treatment was found.
- This method is simple and inexpensive and is a general method that can freely convert the chirality of ⁇ -amino acid in an industrially advantageous manner. Further studies have been made and the present invention has been completed.
- the present invention includes the following contents [1] to [9]. [1] Formula (1)
- R 1 is hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, a substituted Alkenyl group which may be substituted, alkoxy group which may be substituted, cycloalkyl group which may be substituted, aryl group which may be substituted, heteroaryl group which may be substituted, halogen atom or nitro group
- R 2 represents hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, or optionally substituted.
- R 3 and R 4 are each independently hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), and optionally substituted.
- the two R 3 may be the same or different
- the two R 4 may be the same or different
- R 3 and R 4 may form a ring with the carbon atom to which they are attached
- R 5 represents hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, or optionally substituted.
- Two R 5 may be the same or different
- R 6 represents hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group or a halogen atom
- the two R 6 may be the same or different, Two R 6 may form a ring with the carbon atom to which they are attached
- R 7 represents hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.
- R 2 is the formula The compound or a salt thereof according to [1] represented by the formula (2), which represents a group represented by the formula (wherein R 8 represents a hydrogen atom or a halogen atom).
- R 1 is hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, a substituted Alkenyl group which may be substituted, alkoxy group which may be substituted, cycloalkyl group which may be substituted, aryl group which may be substituted, heteroaryl group which may be substituted, halogen atom or nitro group
- R 2 represents hydrogen, an optionally substituted alkyl group, an optionally substituted alkynyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group.
- R 3 and R 4 are each independently hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), and optionally substituted.
- the two R 3 may be the same or different
- the two R 4 may be the same or different
- R 3 and R 4 may form a ring with the carbon atom to which they are attached
- R 5 represents hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, or optionally substituted.
- Two R 5 may be the same or different
- R 6 represents hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group or a halogen atom
- the two R 6 may be the same or different, Two R 6 may form a ring with the carbon atom to which they are attached
- R 7 represents hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group
- R 9 represents an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl
- M represents a divalent metal cation.
- a metal complex represented by [5] In the metal complex represented by the formula (3), in any of the two sets of R 3 and R 4 , in addition to the aromatic ring carbon atom to which R 3 and R 4 are bonded, an aromatic ring or alicyclic group Forming structure, R 2 is the formula (Wherein R 8 represents a hydrogen atom or a halogen atom), the metal complex according to [4] represented by the formula (4).
- R 1 is hydrogen, chlorine, a methyl group or a nitro group, and in any of the two sets of R 3 and R 4 , the aromatic group is further aromatic together with the carbon atom of the aromatic ring to which R 3 and R 4 are bonded.
- the divalent metal cation metal complex represented by the formula is heated under basic conditions to reverse the ⁇ -carbon configuration of the ⁇ -amino acid partial structure, and the configuration is converted by decomposing the metal complex with an acid. To obtain a pure ⁇ -amino acid enantiomer.
- the ⁇ -amino acid or a salt thereof is a mixture of optical isomers or a pure optical isomer having the formula (5) (Wherein R 9 is defined in [4] above), and the method according to [7].
- the divalent metal cation metal complex of the imine compound represented by the formula (3) is heated under basic conditions to convert the ⁇ -carbon configuration of the ⁇ -amino acid partial structure via the enolate intermediate.
- N- represented by the formula (1) according to [1], which is a method for converting the chirality (configuration) of an ⁇ -amino acid, which is an optical activity having a selected R or S configuration.
- R 9 in formula (5) is an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms, other alkynyl groups, alkenyl groups, cycloalkyl groups, aryl groups)
- substituents such as a group
- an alkynyl group which may be substituted an alkenyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, A heteroaryl group which may be substituted, an aralkyl group which may be substituted, or a heteroarylalkyl group which may be substituted
- [8] The method according to [7] above, wherein the ⁇ -amino acid represented by the formula (5) before the chirality conversion is a mixture of optical isomers or a pure
- the present invention aims to produce an optically active ⁇ -amino acid having a desired chirality by converting the chirality of ⁇ -amino acid with high yield and high enantioselectivity, and is an essential chiral template used for this.
- Novel N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compounds and the like are provided.
- the present invention relates to ⁇ -amino acid condensation of optically active N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compounds having axial asymmetry It relates to a metal complex. By passing through the metal complex, the chirality of the ⁇ -amino acid can be easily converted, and an ⁇ -amino acid having the desired chirality can be produced simply and inexpensively.
- FIG. 3 is a diagram showing the results of HPLC analysis of a Ni (II) complex having D-glutamine in a partial structure obtained in Example 2-6.
- FIG. 3 is a diagram showing a 1 H-NMR spectrum of a Ni (II) complex having D-glutamic acid as a partial structure obtained in Example 2-7.
- FIG. 3 is a diagram showing the results of HPLC analysis of L-phenylalanine (ZL-phenylalanine) protected with a Z group obtained in Example 3-1. It is a figure which shows the HPLC analysis result of D-phenylalanine protected by Z group obtained in Example 3-2.
- FIG. 3 is a diagram showing the results of HPLC analysis of a Ni (II) complex having D-glutamine in a partial structure obtained in Example 2-6.
- FIG. 3 is a diagram showing a 1 H-NMR spectrum of a Ni (II) complex having D-glutamic acid as a partial structure obtained in Example 2-7.
- FIG. 3 is
- Example 3 is a diagram showing the results of HPLC analysis of a dicyclohexylamine salt (DCHA salt) of D-lysine (ZD-Lys (Z)) protected with a Z group, obtained in Example 3-3. It is a figure which shows the HPLC analysis result of the Ni (II) complex which has D-phenylalanine in the partial structure obtained in Example 4-1-1. It is a figure which shows the HPLC analysis result of the Ni (II) complex which has D-phenylalanine in the partial structure obtained in Example 4-1-2. It is a figure which shows the HPLC analysis result of the Ni (II) complex which has L-phenylalanine in the partial structure obtained in Example 4-2-1.
- DCHA salt dicyclohexylamine salt
- ZD-Lys (Z) D-lysine protected with a Z group
- the operations (i) and (ii) can be performed continuously.
- the optical isomer of the formula (1A, S form) converts the L-form ⁇ -amino acid into the D-form ⁇ -amino acid by the method of the present invention, but changes the configuration of the D-form ⁇ -amino acid. There is no.
- the optical isomer of formula (1B, R-form) converts D-form ⁇ -amino acid to L-form ⁇ -amino acid by the method of the present invention, but it does not change the configuration of L-form ⁇ -amino acid. Absent.
- the present invention relates to a method for converting L-form ⁇ -amino acid to D-form ⁇ -amino acid by appropriately selecting and using optical isomers of formula (1A, S-form) and formula (1B, R-form),
- the method includes a method of converting a D-type ⁇ -amino acid into an L-type ⁇ -amino acid, and a method of completely converting a racemic ⁇ -amino acid into an ⁇ -amino acid having one optically pure configuration.
- “pure” means that the optical purity is not particularly limited as long as it is industrially satisfactory, and is usually about 90% or more, preferably about 95% or more. .
- the ⁇ -amino acid used in the present invention may be L-form, D-form, or a mixture of any ratio thereof, An ⁇ -amino acid represented by or a salt thereof is preferred.
- R 9 represents an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms, other alkynyl groups, alkenyl groups, cycloalkyl groups, aryl groups, etc.)
- an alkynyl group which may be substituted an alkenyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted
- R 1 is hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, a substituted Alkenyl group which may be substituted, alkoxy group which may be substituted, cycloalkyl group which may be substituted, aryl group which may be substituted, heteroaryl group which may be substituted, halogen atom or nitro group
- R 2 represents hydrogen, an optionally substituted alkyl group, an optionally substituted alkynyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted aryl group
- R 3 and R 4 are each independently hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), and optionally substituted.
- the two R 3 may be the same or different
- the two R 4 may be the same or different
- R 3 and R 4 may form a ring with the carbon atom to which they are attached
- R 5 represents hydrogen, an optionally substituted alkyl group (for example, an alkyl group in which some or all of the hydrogen atoms are substituted with fluorine atoms), an optionally substituted alkynyl group, or optionally substituted.
- Two R 5 may be the same or different
- R 6 represents hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group or a halogen atom
- the two R 6 may be the same or different, Two R 6 may form a ring with the carbon atom to which they are attached
- R 7 represents hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.
- * represents an asymmetric axis. ) It is represented by
- alkyl group in the optionally substituted alkyl group represented by R 1 is not particularly limited, and may be linear or branched.
- examples of the “alkyl group” include an alkyl group having 1 to 20 carbon atoms, and specifically include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and the like.
- Examples include butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, pentadecyl group, hexadecyl group, octadecyl group and the like.
- the “alkynyl group” in the optionally substituted alkynyl group represented by R 1 is not particularly limited. Examples of the “alkynyl group” include alkynyl groups having 2 to 20 carbon atoms, and specific examples include ethynyl group and propynyl group.
- the “alkenyl group” in the optionally substituted alkenyl group represented by R 1 is not particularly limited.
- alkenyl group examples include an alkenyl group having 2 to 20 carbon atoms, and specific examples include a vinyl group, an allyl group, a butenyl group, and a hexenyl group.
- the “alkoxy group” in the optionally substituted alkoxy group represented by R 1 is not particularly limited.
- examples of the “alkoxy group” include, for example, an alkoxy group having 1 to 20 carbon atoms, and specifically include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, Examples thereof include a tert-butoxy group and a pentyloxy group.
- the “cycloalkyl group” in the optionally substituted cycloalkyl group represented by R 1 is not particularly limited.
- Examples of the “cycloalkyl group” include a cycloalkyl group having 3 to 12 carbon atoms, and specifically include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
- the “aryl group” in the optionally substituted aryl group represented by R 1 is not particularly limited.
- the “aryl group” includes, for example, an aryl group having 6 to 20 carbon atoms, and specifically includes a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthryl group, a phenanthryl group, a 2-biphenyl group, Examples include 3-biphenyl group, 4-biphenyl group, terphenyl group and the like.
- the “heteroaryl group” in the optionally substituted heteroaryl group represented by R 1 is not particularly limited.
- the “heteroaryl group” includes, for example, a heteroaryl group preferably containing 1 to 3 atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a hetero atom, specifically, a furanyl group , Thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, phthalazinyl, triazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl Group, dibenzofuranyl group and the like.
- the halogen atom represented by R 1 is not particularly limited. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the “substituent” in R 1 is not particularly limited.
- Examples of the above-mentioned “substituent” include alkyl groups (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, etc.), alkynyl Group (eg, ethynyl group, propynyl group, etc.), alkenyl group (eg, vinyl group, allyl group, butenyl group, hexenyl group, etc.), alkoxy group (eg, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group) Group, sec-butoxy group, tert-butoxy group, pentyloxy group, etc.), cycloalkyl group (eg, cyclopropy
- the number of the “substituents” is not particularly limited.
- the number of the “substituents” may be, for example, 1 to 4, preferably 1 to 2, and more preferably 1.
- the bonding position of R 1 is not particularly limited.
- the bonding position of R 1 may be any of the 3-position, 4-position, 5-position, and 6-position, but the 4-position is preferred.
- An optionally substituted alkyl group represented by R 2 an optionally substituted alkynyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl
- Examples of the group or the optionally substituted heteroaryl group include those exemplified for R 1 .
- Examples of the substituent in this case include the substituents described above for R 1 .
- An optionally substituted alkyl group represented by R 3 or R 4 an optionally substituted alkynyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, or an optionally substituted
- Examples of the preferable cycloalkyl group, the optionally substituted aryl group, the optionally substituted heteroaryl group, and the halogen atom include those exemplified for R 1 .
- Examples of the substituent in this case include the substituents described above for R 1 .
- the ring formed by R 3 and R 4 together with the carbon atom to which they are bonded is not particularly limited, and may be an alicyclic ring or an aromatic ring.
- the ring examples include a cycloalkane ring, a cycloalkene ring, an aryl ring, a heteroaryl ring, and the like, and specifically include a cyclopentane, cyclohexane, cyclopentene, cyclohexene, benzene ring, naphthalene ring, pyridine ring, and the like.
- the number of carbon atoms in the ring is not particularly limited, but preferably 3 to 15 carbon atoms.
- An optionally substituted alkyl group represented by R 5 an optionally substituted alkynyl group, an optionally substituted alkenyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl
- the group, the optionally substituted aryl group, the optionally substituted heteroaryl group, and the halogen atom include those exemplified for R 1 .
- the substituent in this case include the substituents described above for R 1 .
- Examples of the optionally substituted alkyl group, optionally substituted cycloalkyl group or halogen atom represented by R 6 include those exemplified for R 1 .
- Examples of the substituent in this case include the substituents described above for R 1 .
- Examples of the optionally substituted alkyl group, optionally substituted aryl group or optionally substituted heteroaryl group represented by R 7 include those exemplified for R 1 .
- Examples of the substituent in this case include the substituents described above for R 1 .
- R 1 is preferably hydrogen, chlorine, a methyl group or a nitro group.
- R 2 is preferably an aryl group which may be substituted, and more preferably a phenyl group or a group obtained by substituting a phenyl group with a halogen atom.
- the two R 3 are preferably the same. Moreover, it is preferable that two R ⁇ 4 > is the same. R 3 and R 4 more preferably form a ring together with the carbon atom to which they are bonded.
- Two R 5 are preferably the same, and more preferably, both R 5 are hydrogen.
- the two R 6 are preferably the same, and more preferably the two R 6 are both hydrogen.
- the “asymmetric axis” indicated by * means a coupled axis that generates chirality by limiting the rotation of the axis.
- a coupled axis that generates chirality by limiting the rotation of the axis.
- the compound represented by the formula (1) has the formula (2) in which R 3 and R 4 form an aromatic ring or an alicyclic structure together with the carbon atom to which they are bonded.
- R 8 represents a hydrogen or halogen atom. It is preferable that it is a compound represented by these.
- R 8 examples include those exemplified for R 1 .
- R 8 is preferably hydrogen, fluorine or chlorine.
- Examples of the compound represented by the formula (2) or a salt thereof include compounds represented by the following structural formulas (2-1) to (2-7) or a salt thereof.
- Examples of the salt of the optically active N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compound in the present invention include hydrochloric acid, sulfuric acid, phosphorus Examples thereof include salts with inorganic acids such as acids, and salts with organic acids such as acetic acid and benzenesulfonic acid.
- the method for producing the compound represented by the formula (1) or a salt thereof is not particularly limited, but can be produced, for example, by the following reaction: Formula (7)
- the compound represented by Formula (1) or its salt can be manufactured by making the compound represented by these, or its salt react.
- the compound represented by the formula (7) or a salt thereof may be produced by a known method, or a commercially available product may be used.
- As the compound represented by the formula (7) or a salt thereof for example, substances described in the literature (T. K. Ellis et al., J. Org. Chem., 2006, 71, 8572-8578.) Can be used.
- the compound represented by formula (7) is represented by formula (7-1).
- R 1 and R 8 are as defined above. It is preferable that it is a compound represented by these.
- examples of R 1 include those exemplified in the formula (1).
- examples of R 8 include those exemplified in the formula (2).
- L 1 and L 2 each independently represent a leaving group.
- the leaving group is not particularly limited as long as it is generally a known group as the leaving group, and examples thereof include halogen atoms, tosylate (OTs), and mesylate (OMs).
- L 1 and L 2 are preferably halogen atoms, and more preferably chlorine atoms or bromine atoms.
- L 1 and L 2 are preferably the same group, and more preferably a halogen atom.
- Examples of the compound represented by the formula (8) include ClCH 2 COCl, BrCH 2 COBr, and the like.
- the compound represented by the formula (8) or a salt thereof can be produced by a known method.
- an acetanilide compound derived from a compound represented by the formula (8) for example, substances described in the literature (T. K. Ellis et al., J. Org..Chem., 2006, 71, 8572-8578.) Can be used.
- the compound represented by the formula (9) or a salt thereof can be produced by a known method.
- the compound represented by the formula (9) can be produced, for example, by the method described in the literature (N. Maigrot et al., J. Org. Chem., 1985, 50, 3916-3918.).
- the compound represented by the formula (9) has the formula (10)
- R 5 and * are as defined above. It is preferable that it is a compound represented by these.
- R 5 and R 7 include those exemplified in the formula (1).
- the amount of the compound represented by formula (8) or a salt thereof is not particularly limited as long as the reaction proceeds. Specifically, the amount of the compound represented by the formula (8) or a salt thereof is specifically about 0.5 to 10 mol per mol of the compound represented by the formula (7) or a salt thereof, for example. The amount is preferably about 1.0 to 3.0 mol.
- the amount of the compound represented by the formula (9) or a salt thereof is not particularly limited as long as the reaction proceeds. Specifically, the amount of the compound represented by the formula (9) or a salt thereof is specifically about 0.5 to 5.0 moles per 1 mole of the compound represented by the formula (7) or a salt thereof, for example. About 0.5 to 2.0 mol is preferred.
- the solvent used for the reaction is not particularly limited, but examples thereof include alcohols (methanol, ethanol, isopropyl alcohol, tert-butanol, etc.), ethers ( Diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.), halogen hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.), aromatic hydrocarbons (benzene, toluene) , Xylene, pyridine, etc.), aliphatic hydrocarbons (hexane, pentane, cyclohexane, etc.), nitriles (acetonitrile, propionitrile, etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, N -
- the base used in the reaction is not particularly limited as the base used in the reaction.
- potassium hydroxide, sodium hydroxide, water Lithium oxide, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate, potassium acetate, lithium acetate, sodium benzoate, lithium benzoate, etc. among these, potassium hydroxide from the viewpoint of reaction efficiency Sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate and the like are preferable.
- An optically pure target substance can be obtained with a well-known separation / purification method.
- Known separation / purification methods include, for example, concentration; extraction; filtration; washing; crystallization; recrystallization; salt formation with achiral acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and recrystallization thereof.
- a separation / purification step may be further performed in the production method of the compound represented by the formula (1) or a salt thereof.
- the purification method is not particularly limited, and various methods usually used in this field may be adopted.
- Specific examples of the separation method include concentration, extraction, filtration, washing, and the like.
- Specific examples of the purification method include a crystallization method (recrystallization or suspension), a selective dissolution method, and the like.
- recrystallization examples include a method of forming a salt with an achiral acid (hydrochloric acid, sulfuric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, etc.) and then recrystallization, or a chiral acid (mandelic acid, tartaric acid, dibenzoyltartaric acid, And diastereomer salt method using ditoluoyltartaric acid, 10-camphorsulfonic acid, malic acid).
- achiral acid hydrochloric acid, sulfuric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, etc.
- a chiral acid mandelic acid, tartaric acid, dibenzoyltartaric acid, And diastereomer salt method using ditoluoyltartaric acid, 10-camphorsulfonic acid, malic acid.
- the metal complex represented by the formula (3) is also a constituent of the present invention.
- R 9 is an optionally substituted alkyl group, an optionally substituted alkynyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, a substituted Represents an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, and M represents a divalent metal cation.
- examples of R 1 to R 6 include those exemplified by the formula (1).
- M represents a divalent metal cation.
- alkaline-earth metal cations such as magnesium, calcium, strontium, barium; cadmium, titanium, zirconium, nickel (II), palladium, platinum, zinc, copper (II ), Mercury (II), iron (II), cobalt (II), tin (II), lead (II), manganese (II) and other transition metal cations.
- nickel, copper, palladium or platinum cations are preferable.
- an optionally substituted alkyl group represented by R 9 an optionally substituted alkynyl group, an optionally substituted alkenyl group, or an optionally substituted
- the preferable cycloalkyl group, the optionally substituted aryl group, and the optionally substituted heteroaryl group include those exemplified for R 1 .
- the optionally substituted aralkyl group represented by R 9 include those in which the hydrogen atom of the above-described alkyl group is substituted with an aryl group, specifically, a benzyl group, a phenylethyl group, a phenylpropyl group. And naphthylmethyl group.
- heteroaryl group in the optionally substituted heteroarylalkyl group represented by R 9 , for example, an atom selected from a nitrogen atom, a sulfur atom and an oxygen atom is preferably used as a hetero atom, preferably 1 to 3
- Specific examples include a heteroaryl group containing, specifically, a furanyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, Examples include phthalazinyl group, triazinyl group, indolyl group, isoindolyl group, quinolinyl group, isoquinolinyl group, dibenzofuranyl group and the like.
- the partial structure derived from ⁇ -amino acid containing R 9 has an asymmetric center. Further, the metal complex represented by the formula (3) has axial asymmetry in the partial structure of biphenyl as indicated by *.
- the metal complex represented by the formula (3) has the formula (4) in which R 3 and R 4 form an aromatic ring or an alicyclic structure together with the carbon atom to which they are bonded.
- examples of R 1 , R 5 and R 6 include those exemplified in the formula (1).
- examples of R 9 and M include those exemplified in the formula (3).
- R 8 for example, such as those exemplified in formula (2).
- each symbol has the same meaning as the above formula (3).
- the metal complex represented by these can be obtained.
- Examples of the ⁇ -amino acid represented by the formula (5) or a salt thereof include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), and glutamic acid.
- Glu histidine
- His isoleucine
- Ile isoleucine
- Leu leucine
- Lysine isoleucine
- Met methionine
- Met phenylalanine
- Ser serine
- Thr threonine
- Trp tryptophan
- ⁇ -amino acids such as (Tyr) and valine (Val)
- ⁇ -amino acids or salts thereof may be L-form, D-form, or a mixture thereof in any proportion.
- the raw material ⁇ -amino acid of formula (5) or a salt thereof and a compound represented by formula (1) or a salt thereof and a metal compound represented by formula (6) or a salt thereof were mixed. It is preferable to heat afterwards. Thereby, the metal complex represented by Formula (3) which is a target substance can be obtained with a higher chemical yield.
- Alcohols are used as the solvent used in the formation of the metal complex, and methanol, ethanol, isopropyl alcohol, tert-butanol, and tert-amyl alcohol are preferable.
- the amount of the solvent to be used is not particularly limited, but it can usually be about 1.0 to 150 times the volume, and about 5 to 50 times the volume based on 1 part by weight of the compound represented by the formula (1). preferable.
- the amount of ⁇ -amino acid represented by the formula (5) or a salt thereof is not particularly limited.
- the amount of the ⁇ -amino acid represented by the formula (5) or a salt thereof can be usually about 0.1 to 10 mol per 1 mol of the compound represented by the formula (1) or a salt thereof, More preferably, it is about 0.3 to 5 moles.
- the amount of the metal compound represented by the formula (6) is not particularly limited.
- the amount of the metal compound represented by the formula (6) to be used can be usually about 0.1 to 10 mol, and about 0.5 to 1 mol of the compound represented by the formula (1) or a salt thereof. It is preferably ⁇ 8.0 mol.
- a reaction of a compound represented by formula (7) or a salt thereof with a compound represented by formula (8) or a salt thereof and a compound represented by formula (9) or a salt thereof for example, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and lithium hydroxide are preferable.
- the amount of base used is not particularly limited.
- the amount of the base to be used can be generally about 0.1 to 20 mol, preferably 0.5 to 10 mol, relative to 1 mol of the compound represented by formula (1).
- the reaction time of the present invention is not particularly limited.
- the reaction time is usually about 0.1 to 72 hours, preferably 0.1 to 48 hours, and particularly preferably 0.1 to 20 hours.
- the pressure at which the reaction is performed is not particularly limited, and the reaction may be performed under normal pressure, under pressure, or under reduced pressure.
- the pressure for carrying out the above reaction can usually be about 0.1 to 10 atm.
- the configuration of the ⁇ carbon in the amino acid partial structure of the metal complex (3) is easily converted by heating. Therefore, the metal complex (3) may be converted after the isolation and heating to convert the ⁇ -carbon configuration of the amino acid partial structure, or the ⁇ -carbon configuration may be changed by heating during the metal complex formation reaction. You may do it at the same time.
- the compound represented by the formula (1) or a salt thereof is represented by the formula (1A, S form).
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and * are as defined above, or a salt thereof.
- the product is derived from the ⁇ -amino acid of the metal complex represented by the formula (3) as a product.
- the chirality of the partial structure is converted to L-type by heating under basic conditions, but when the ⁇ -amino acid represented by the formula (5) as a reaction raw material or a salt thereof has L-type configuration In the metal complex represented by the formula (3) as a product, the configuration of the partial structure derived from the ⁇ -amino acid is not changed and remains in the L-type.
- the above production method appropriately selects an optical isomer of N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compound.
- the configuration of the partial structure derived from ⁇ -amino acid is converted. That is, the above production method uses an ⁇ -amino acid represented by the formula (5) and having the L-type configuration as a raw material, and has a partial structure derived from an ⁇ -amino acid represented by the formula (3 ′) and containing R 10 .
- the optical isomer of the N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compound should be appropriately selected.
- racemic form of the ⁇ -amino acid represented by the formula (5) is used as a raw material, and the configuration of the partial structure derived from the ⁇ -amino acid represented by the formula (3 ′) and containing R 10 is L-form.
- the solvent used in the above chirality conversion alcohols are used, and methanol, ethanol, isopropyl alcohol, tert-butanol, tert-amyl alcohol, and methyl isobutyl ketone are preferable.
- the amount of the solvent to be used is not particularly limited, but it can usually be about 1.0 to 150 times the volume, and about 5 to 50 times the volume based on 1 part by weight of the compound represented by the formula (1). preferable.
- the alcohol solution of the metal complex represented by the formula (3) is usually heated to about 40 to 80 ° C. for about 0.5 to 24 hours, whereby the ⁇ carbon of the ⁇ -amino acid partial structure is heated. The configuration is converted.
- the pressure at which the reaction is carried out is not particularly limited, and the reaction may be carried out under any conditions of normal pressure, increased pressure, and reduced pressure.
- the pressure for carrying out the above reaction can usually be about 0.1 to 10 atm.
- an optically pure target substance can be obtained by a known separation / purification method after the reaction.
- a known separation / purification method for example, phase transfer, concentration, chromatography, crystallization, distillation and the like can be mentioned.
- R 10 has the same meaning as R 9 above, and ** represents an asymmetric carbon atom. However, the configuration of the ⁇ carbon is converted from the compound represented by the formula (5).)
- An ⁇ -amino acid having a desired chirality represented by the formula (1) or a salt thereof can be produced.
- the configuration of the ⁇ -amino acid represented by the formula (5 ′) or a salt thereof is the same as the configuration of the ⁇ -amino acid partial structure in the metal complex represented by the formula (3 ′).
- the acid used in the above production method is not particularly limited and may be a known acid.
- the acid may be an inorganic acid or an organic acid.
- the inorganic acid include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and perchloric acid.
- the organic acid include acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, propionic acid, butyric acid, valeric acid and the like.
- Hydrochloric acid, sulfuric acid, trifluoroacetic acid and methanesulfonic acid are preferred, and hydrochloric acid and methanesulfonic acid are more preferred.
- the amount of acid used is not particularly limited.
- the amount of the acid used is usually about 0.1 to 20 mol, preferably about 0.3 to 10 mol, relative to 1 mol of the metal complex represented by the formula (3 ′), for example.
- the solvent used in the production method is preferably an alcohol, and more preferably methanol or ethanol.
- the amount of the solvent used is usually about 0.1 to 100 times, preferably 0.5 to 50 times the volume of 1 part by weight of the metal complex represented by the formula (3 ′).
- the reaction temperature is usually about 0 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C., more preferably 5 ° C. to 60 ° C., and more preferably 40 ° C. to 60 ° C. It is particularly preferred.
- the reaction time is usually about 0.1 to 72 hours, preferably about 0.1 to 48 hours, and particularly preferably about 0.1 to 20 hours.
- the pressure at which the reaction is carried out in the above production method is not particularly limited, and can be, for example, about 0.1 to 10 atmospheres.
- an optically pure target substance can be obtained by a known separation / purification method after the reaction.
- each symbol has the same meaning as the above formula (5 ′).
- An ⁇ -amino acid having a desired chirality or a salt thereof can be produced.
- Examples of the ⁇ -amino acid represented by the formula (5 ′) include those exemplified in the above formula (5).
- the configuration at the ⁇ -carbon of the ⁇ -amino acid represented by (5 ′) or a salt thereof is converted from the ⁇ -amino acid represented by formula (5) or a salt thereof.
- HPLC measurement conditions In Examples and Reference Examples, measurement was performed under the following HPLC conditions.
- ⁇ HPLC condition-2 Z-Phe chiral analysis condition 1>
- Column: CHIRALCELL OJ-RH (5 ⁇ m, 150 x 4.6 mm id) Eluent: A: B 65:35 (0 to 30 min)
- A 0.1% phosphoric acid aqueous solution
- B 0.1% acetonitrile containing phosphoric acid
- ⁇ HPLC condition-2 Z-Phe chiral analysis condition 2>
- ⁇ HPLC condition-4 ZD-Lys (Z) chiral analysis condition>
- Column: CHIRALPAK AS-RH (5 ⁇ m, 150 x 4.6 mm id) Eluent: A: B 60: 40 (0 to 12 min)
- B acetonitrile Flow rate: 1.0 mL / min Temp: 25 °C Detector: UV 200 nm
- Example 1 Synthesis of Chiral Template (Chiral Auxiliary)
- Example 1-1 (S) -N- (2-Benzoylphenyl) -2- [3,5-dihydro-4H-dinaphtho [2,1-c: 1 ′, Synthesis of 2'-e] azepine-4-yl] acetamide
- Example 2 Inversion reaction Example 2-1: Synthesis of D-phenylalanine by chiral inversion reaction of L-phenylalanine: Synthesis of Ni complex having D-phenylalanine as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 30 minutes to precipitate crystals, and filtered. 50 crystals collected by filtration Ni (II) complex having a partial structure of D-phenylalanine (0.246 g, yield 90.5%, 98% de) was obtained as red crystals by air drying at ° C.
- Example 2-2 Synthesis of L-phenylalanine by chiral inversion reaction of D-phenylalanine: Synthesis of Ni complex having L-phenylalanine as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (60 mL), stirred for 30 minutes to precipitate crystals, and filtered. 50 crystals collected by filtration Ni (II) complex having a partial structure of L-phenylalanine (0.493 g, yield 90.6%, 97% de) was obtained as red crystals by air drying at ° C.
- Example 2-3 Synthesis of D-leucine by chiral inversion reaction of L-leucine: Synthesis of Ni complex having D-leucine as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 30 minutes to precipitate crystals, and filtered.
- the crystal collected by filtration was vacuum-dried at 40 ° C. to obtain a Ni (II) complex having a partial structure of D-leucine (0.116 g, yield 89.1%, 91.6% de) as a red crystal.
- Example 2-4 Synthesis of D-methionine by chiral inversion reaction of L-methionine: Synthesis of Ni complex having D-methionine as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (20 mL), stirred for 30 minutes to precipitate crystals, and filtered.
- the crystals collected by filtration were vacuum-dried at 50 ° C. to obtain Ni (II) complex (0.129 g, yield 97.2%, 93.3% de) having D-methionine as a partial structure as red crystals.
- Example 2-5 Synthesis of D-tryptophan by chiral inversion reaction of L-tryptophan: Synthesis of Ni complex having D-tryptophan as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (70 mL), stirred for 30 minutes to precipitate crystals, and filtered.
- the collected crystals were vacuum dried at 50 ° C. to obtain Ni (II) complex (0.602 g, yield 84.3%, 99.4% de) having D-tryptophan as a partial structure as red crystals.
- Example 2-6 Synthesis of D-glutamine by chiral inversion reaction of L-glutamine: Synthesis of Ni complex having D-glutamine as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 1 hour to precipitate crystals, and filtered.
- the collected crystals were vacuum dried at 40 ° C. to obtain Ni (II) complex (0.116 g, yield 87.3%, 94.2% de) having D-glutamine as a partial structure as red crystals.
- Example 2-7 Synthesis of D-glutamic acid by chiral inversion reaction of L-glutamic acid: Synthesis of Ni complex having D-glutamic acid as a partial structure
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 1 hour to precipitate crystals, and filtered.
- the crystals collected by filtration were vacuum-dried at 40 ° C to obtain a Ni (II) complex with a partial structure of D-glutamic acid (0.110 g, yield 82.5%, 91.8% de (determined based on 1 H-NMR spectrum)). Obtained as red crystals.
- Example 2-8 Synthesis of D-lysine by chiral inversion reaction of L-lysine: Synthesis of Ni complex having D-lysine as a partial structure
- dichloromethane (5 mL) and 5% aqueous acetic acid solution (5 mL) were added to the reaction solution to separate the layers, and then dichloromethane and methanol were added to the organic layer. Washed with (5 mL). The concentrated residue of the organic layer was stirred and washed in dichloromethane (1 mL) and ethyl acetate (6 mL), and the filtered solid was blown and dried at 50 ° C., and Ni (II) having D-lysine as a partial structure. The complex (0.323 g, 81.2% yield) was obtained as a red solid.
- Example 3-1 Release of L-phenylalanine by acid conditions of Ni (II) complex having a partial structure of L-phenylalanine obtained by deracemization of phenylalanine racemate or chirality inversion reaction of D-phenylalanine, and Z group Protection by
- the obtained organic layer was dried over sodium sulfate, and the sodium sulfate was removed by filtration and then concentrated to dryness to recover the chiral auxiliary (0.27 g, yield 90%) as a pale yellow solid.
- the aqueous ammonia layer and aqueous layer extract were combined and concentrated to dryness, and the resulting solid was dissolved in 9% aqueous ammonia (3 mL) and dissolved in a cation exchange resin column (Mitsubishi Chemical Corporation, trade name [SK -1B], 9 mL, eluent: passing water followed by aqueous ammonia (2% ⁇ 8%)) to give phenylalanine (0.083 g, crude product).
- Example 3-2 Release of D-phenylalanine by acid conditions of Ni (II) complex having a partial structure of D-phenylalanine obtained by deracemization of phenylalanine racemate or chirality inversion reaction of L-phenylalanine, and Z group Protection by
- the obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (4 mL), water (4 mL) and saturated brine (4 mL), and dried over sodium sulfate. After removing sodium sulfate by filtration and concentrating to dryness, the chiral auxiliary (0.29 g, yield 96%) was recovered as a pale yellow solid. On the other hand, after concentrating and drying the aqueous layer extract (12 mL), the resulting solid was dissolved in 13% aqueous ammonia (4 mL) and dissolved in a cation exchange resin column (trade name [SK-1B, manufactured by Mitsubishi Chemical Corporation].
- the reaction mixture was concentrated, and water (17 mL) and toluene (1 mL) were added to separate the layers.
- the organic layer was washed with water (2 mL) and saturated brine (2 mL, 3 times), dried over sodium sulfate, and concentrated to give a yellow oil (0.161 g, crude product, quantitative).
- the obtained yellow oily substance was dissolved in isopropyl alcohol (0.01 mL) -ethyl acetate (0.6 mL), and a solution of dicyclohexylamine (0.097 g, 1 eq.) In ethyl acetate (0.1 mL) was added. 0.9 mL) and hexane (3 mL) were added and stirred at room temperature overnight. The precipitated crystals were collected by filtration and dried in vacuo at 50 ° C. to obtain ZD-phenylalanine / DCHA salt (0.247 g, yield 96%, 99.0% ee, abbreviated as Z-Phe) as white crystals. It was.
- Example 3-3 Release of D-lysine under acidic conditions of a Ni (II) complex having a partial structure of D-lysine obtained by the chirality inversion reaction of L-lysine and protection by a Z group 1N hydrochloric acid (1.6 mL, 6 eq.) was added to a methanol suspension (6 mL) of Ni (II) complex (0.2 g, 0.27 mmoL) having D-lysine as a partial structure, and the mixture was stirred at 40 ° C for 4 hours. Stir. After completion of the reaction, the reaction mixture was concentrated, the residue was dissolved by adding ethyl acetate (10 mL), and the organic layer was extracted with water (10 mL, once, 5 mL, twice).
- the obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (5 mL), water (5 mL), and saturated brine (5 mL), and then dried over sodium sulfate. The sodium sulfate was removed by filtration and then concentrated to dryness to recover the chiral auxiliary (0.14 g, yield 93%) as a pale yellow solid.
- the aqueous layer extract (20 mL) was washed with a small amount of methylene chloride and then concentrated to dryness. The solid obtained was dissolved in water-methanol and a small amount of aqueous ammonia (1 mL) to dissolve the cation exchange resin.
- D-lysine (0.038 g, crude product) was obtained by passing through a column (Mitsubishi Chemical Co., Ltd., trade name [SK-1B], 3 mL, eluent: water, then aqueous ammonia (8%)). .
- Add sodium bicarbonate (0.079 mg, 4 eq.)-Sodium carbonate (0.050 mg, 2 eq.) In water (1 mL) and THF (1 mL) to D-lysine (0.034 g) and dissolve in an ice bath.
- a THF solution (2.5 mL) of N-benzyloxycarbonyloxysuccinimide (0.118 g, 2 eq.) was added, and the mixture was stirred at room temperature for 2 hours.
- Example 4 Deracemization reaction Example 4-1: Synthesis of D-phenylalanine by deracemization of DL-phenylalanine
- Example 4-1-1 When DL-phenylalanine (2 equivalents), nickel acetate tetrahydrate (2 equivalents) and potassium carbonate (6 equivalents) were used with respect to the chiral auxiliary.
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 30 minutes to precipitate crystals, and filtered. 50 crystals collected by filtration Ni (II) complex having a partial structure of D-phenylalanine (0.234 g, yield 86%, 99% de) was obtained as red crystals by air drying at ° C.
- D-phenylalanine can be obtained by treating this complex in the same manner as in Example 3.
- Example 4-1-2 When DL-phenylalanine (1.1 eq), nickel acetate tetrahydrate (1.1 eq) and potassium carbonate (4 eq) were used with respect to the chiral auxiliary
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 30 minutes to precipitate crystals, and filtered. 50 crystals collected by filtration Ni (II) complex having a partial structure of D-phenylalanine (0.246 g, yield 90.5%, 97.2% de) was obtained as red crystals by air drying at ° C.
- D-phenylalanine can be obtained by treating this complex in the same manner as in Example 3.
- Example 4-2 Synthesis of L-phenylalanine by deracemization of DL-phenylalanine
- Example 4-2-1 When DL-phenylalanine (2 equivalents), nickel acetate tetrahydrate (2 equivalents) and potassium carbonate (6 equivalents) were used with respect to the chiral auxiliary
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (120 mL), stirred for 30 minutes to precipitate crystals, and filtered. 50 crystals collected by filtration Ni (II) complex having a partial structure of L-phenylalanine (1.035 g, yield 95.2%, 99% de) was obtained as red crystals by air drying at ° C.
- L-phenylalanine can be obtained by treating this complex in the same manner as in Example 3.
- Example 4-2-2 When DL-phenylalanine (1.1 eq), nickel acetate tetrahydrate (1.1 eq) and potassium carbonate (4 eq) were used with respect to the chiral auxiliary
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (30 mL), stirred for 30 minutes to precipitate crystals, and filtered.
- the crystal collected by filtration was blown and dried at 50 ° C. to obtain a Ni (II) complex having a partial structure of L-phenylalanine (0.250 g, yield 92.1%, 97% de) as red crystals.
- L-phenylalanine can be obtained by treating this complex in the same manner as in Example 3-1.
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 30 minutes to precipitate crystals, and filtered.
- the crystals collected by filtration were blown and dried at 50 ° C. to obtain Ni (II) complex (0.203 g, yield 79.6%, 92.4% de) having D-valine as a partial structure as red crystals.
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (30 mL), stirred for 30 minutes to precipitate crystals, and filtered.
- the crystals collected by filtration were blown and dried at 50 ° C. to obtain Ni (II) complexes (0.232 g, yield 91.0%, 95% de) having L-valine as a partial structure as red crystals.
- L-valine can be obtained by treating this complex in the same manner as in Example 3.
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (15 mL), stirred for 30 minutes to precipitate crystals, and filtered. The crystals collected by filtration were blown and dried at 50 ° C. to obtain Ni (II) complex (0.208 g, yield 84.8%, 95.8% de) having D-alanine as a partial structure as red crystals.
- D-alanine can be obtained by treating this complex in the same manner as in Example 3.
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (30 mL), stirred for 30 minutes to precipitate crystals, and filtered. 50 crystals collected by filtration Ni (II) complex having a partial structure of L-alanine (0.207 g, yield 84.8%, 96% de) was obtained as red crystals by air drying at ° C.
- reaction solution was added to an ice-cooled 5% aqueous acetic acid solution (80 mL) and stirred for 30 minutes.
- the precipitated crystals were collected by filtration and dried in vacuo at 50 ° C to obtain Ni (II) complex (0.273 g, 98.4% yield, 92.6% de) with D-tyrosine as a partial structure as an orange-red solid. It was.
- an optically active substance of a novel N- (2-acylaryl) -2- [5,7-dihydro-6H-dibenzo [c, e] azepin-6-yl] acetamide compound is appropriately used as a chiral template.
- the ⁇ -amino acid having the desired chirality can be obtained with high yield and high enantioselectivity by converting the chirality of the ⁇ -amino acid. It is particularly useful for the production of unnatural optically active ⁇ -amino acids.
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Abstract
Description
光学活性α-アミノ酸の製造方法として、古典的にはα-アミノ酸のラセミ体の光学分割があり、近年では発酵法や酵素法によりL-α-アミノ酸が容易に得られるようになった。D-α-アミノ酸については、ラセミ体の脱ラセミ化反応や容易に得られるL-α-アミノ酸からのキラリティの変換反応が研究されてきた。このような方法としては、例えば不斉炭素原子を有するキラルリガンドを用いる方法(非特許文献1等参照)、軸不斉を有するキラルリガンドを用いる方法(非特許文献2、特許文献1、2等参照)等が報告されている。
しかしいずれの方法も一般に変換反応の速度が遅く、特にバリンやイソロイシン等の立体的にかさ高い側鎖を有するアミノ酸では反応速度が非常に遅く、かつ生成物の光学純度が低い等の問題がある。
[1] 式(1)
R2は水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R3、R4は、それぞれ独立して、水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又はハロゲン原子を表し、
2つのR3は同一であっても異なっていてもよく、
2つのR4は同一であっても異なっていてもよく、
R3とR4はそれらが結合する炭素原子と共に環を形成してもよく、
R5は、水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、カルボキシル基、ハロゲン原子、―COOR7又は-C(OH)(R7)2を表し、
2つのR5は同一であっても異なっていてもよく、
R6は、水素、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基又はハロゲン原子を表し、
2つのR6は同一であっても異なっていてもよく、
2つのR6はそれらが結合する炭素原子と共に環を形成してもよく、
R7は水素、置換されていてもよいアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表す。*は不斉軸を表す。)
で表される化合物又はその塩。
[2] 式(1)で表される化合物において二組のR3とR4のいずれの組においてもR3とR4が結合している芳香環の炭素原子と共にさらに芳香環又は脂環式構造を形成し、
R2が式
[3] R1が水素、塩素、メチル基又はニトロ基であり、R5及びR6がいずれも水素である[2]に記載の化合物又はその塩。
[4] 式(3)
R2は水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R3、R4は、それぞれ独立して、水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又はハロゲン原子を表し、
2つのR3は同一であっても異なっていてもよく、
2つのR4は同一であっても異なっていてもよく、
R3とR4はそれらが結合する炭素原子と共に環を形成してもよく、
R5は、水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、カルボキシル基、ハロゲン原子、―COOR7又は-C(OH)(R7)2を表し、
2つのR5は同一であっても異なっていてもよく、
R6は、水素、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基又はハロゲン原子を表し、
2つのR6は同一であっても異なっていてもよく、
2つのR6はそれらが結合する炭素原子と共に環を形成してもよく、
R7は水素、置換されていてもよいアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R9は置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよいアラルキル基又は置換されていてもよいヘテロアリールアルキル基を表し、*は不斉軸を表す。Mは2価の金属カチオンを表す。)
で表される金属錯体。
[5] 式(3)で表される金属錯体において二組のR3とR4いずれの組においてもR3とR4が結合している芳香環の炭素原子と共にさらに芳香環または脂環式構造を形成し、
R2が式
[6] R1が水素、塩素、メチル基又はニトロ基であり、二組のR3とR4のいずれの組においてもR3とR4が結合している芳香環の炭素原子と共にさらに芳香環または脂環式構造を形成し、R5及びR6がいずれも水素であり、Mがニッケル、銅、パラジウムまたは白金カチオンである[4]又は[5]に記載の金属錯体。
[7] α―アミノ酸の立体配置を変換させる方法であって、選択されたRまたはS体の光学活性である請求項1に記載の式(1)で表されるN-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物又はその塩とα-アミノ酸より生じたイミン化合物の請求項4に記載の式(3)で表される二価金属カチオン金属錯体を、塩基性条件下で加熱することで、α-アミノ酸部分構造のα炭素の立体配置を反転させ、酸により金属錯体を分解することで立体配置が変換した純粋なα-アミノ酸エナンチオマーを得る方法。
[8] α-アミノ酸またはその塩が、光学異性体の混合物または純粋な光学異性体であって式(5)
[8] キラリティを変換させる前の式(5)で表わされるα―アミノ酸が光学異性体の混合物または純粋な光学異性体である上記[7]記載の方法。
[9] N-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物が上記[1]に記載の式(1)の化合物である上記[7]および[8]に記載の方法。
本発明の反応チャートは下記の通りである。
(i)一般式(1)の光学活性N-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物と一般式(5)のα-アミノ酸との縮合反応によって生じたイミン化合物に金属塩MXnを反応させて一般式(3)の金属錯体を生成させ;
(ii)一般式(3)の金属錯体を塩基性条件下で加熱して、式(3´)で示される、α-アミノ酸部分構造の立体配置が変換した金属錯体に導き;
(iii)立体配置の変換した一般式(3´)の金属錯体を酸分解することによって立体配置が変換した式(5´)のα-アミノ酸を製造する。
上記(i)および(ii)の操作は連続して行うことができる。
一般式(1)の化合物には、式(1A、S体)と式(1B、R体)で表される2種類の光学異性体が存在する。式(1A、S体)の光学異性体は、本発明の方法により、L型のα-アミノ酸をD型のα-アミノ酸に変換するが、D型のα-アミノ酸の立体配置を変化させることはない。又式(1B、R体)の光学異性体は本発明の方法により、D型のα-アミノ酸をL型のα-アミノ酸に変換するがL型のα-アミノ酸の立体配置を変化させることはない。
即ち、本発明は、式(1A、S体)および式(1B、R体)の光学異性体を適宜選択して使用することによるL型α-アミノ酸をD型α-アミノ酸に変換する方法、D型α-アミノ酸をL型α-アミノ酸に変換する方法、及び、ラセミ型のα-アミノ酸を光学的に純粋な一方の立体配置を有するα-アミノ酸に完全に変換する方法を含むものである。
なお、本発明において「純粋な」とは、光学純度が、工業的に支障の無いレベルであればよく、特に限定されないが、通常約90%以上、好ましくは約95%以上である状態をいう。
本発明方法により高収率で高エナンチオ選択的に所望の光学活性アミノ酸を製造することができる。
(式中、R1は水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、ハロゲン原子又はニトロ基を表し、
R2は水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R3、R4は、それぞれ独立して、水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又はハロゲン原子を表し、
2つのR3は同一であっても異なっていてもよく、
2つのR4は同一であっても異なっていてもよく、
R3とR4はそれらが結合する炭素原子と共に環を形成してもよく、
R5は、水素、置換されていてもよいアルキル基(例えば、一部又は全部の水素原子が弗素原子で置換されているアルキル基)、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、カルボキシル基、ハロゲン原子、―COOR7又は-C(OH)(R7)2を表し、
2つのR5は同一であっても異なっていてもよく、
R6は、水素、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基又はハロゲン原子を表し、
2つのR6は同一であっても異なっていてもよく、
2つのR6はそれらが結合する炭素原子と共に環を形成してもよく、
R7は水素、置換されていてもよいアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表す。*は不斉軸を表す。)
で表される。
R1で表される置換されていてもよいアルキニル基における「アルキニル基」は、特に限定されない。上記「アルキニル基」としては、例えば炭素数2~20のアルキニル基などが挙げられ、具体的にはエチニル基、プロピニル基などが挙げられる。
R1で表される置換されていてもよいアルケニル基における「アルケニル基」は、特に限定されない。上記「アルケニル基」として、例えば炭素数2~20のアルケニル基などが挙げられ、具体的にはビニル基、アリル基、ブテニル基、ヘキセニル基などが挙げられる。
R1で表される置換されていてもよいアルコキシ基における「アルコキシ基」は、特に限定されない。上記「アルコキシ基」としては、例えば炭素数1~20のアルコキシ基などが挙げられ、具体的にはメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、sec-ブトキシ基、tert-ブトキシ基、ペンチルオキシ基などが挙げられる。
R1で表される置換されていてもよいシクロアルキル基における「シクロアルキル基」は、特に限定されない。上記「シクロアルキル基」としては、例えば炭素数3~12のシクロアルキル基などが挙げられ、具体的にはシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基などが挙げられる。
R1で表される置換されていてもよいアリール基における「アリール基」は、特に限定されない。上記「アリール基」としては、例えば炭素数6~20のアリール基などが挙げられ、具体的にはフェニル基、1-ナフチル基、2-ナフチル基、アントリル基、フェナントリル基、2-ビフェニル基、3-ビフェニル基、4-ビフェニル基、ターフェニル基などが挙げられる。
R1で表される置換されていてもよいヘテロアリール基における「ヘテロアリール基」は、特に限定されない。上記「ヘテロアリール基」としては、例えば窒素原子、硫黄原子及び酸素原子などから選択される原子を異項原子として好ましくは1~3個含有するヘテロアリール基が挙げられ、具体的にはフラニル基、チエニル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、ピロリル基、イミダゾリル基、ピラゾリル基、ピリジル基、ピリミジニル基、ピラジニル基、フタラジニル基、トリアジニル基、インドリル基、イソインドリル基、キノリニル基、イソキノリニル基、ジベンゾフラニル基などが挙げられる。
R1で表されるハロゲン原子は、特に限定されない。上記ハロゲン原子としては、例えばフッ素原子、塩素原子、臭素原子、ヨウ素原子などが挙げられる。
R1の結合位置は、特に限定されない。R1の結合位置は、3位、4位、5位、6位のいずれであってもよいが、4位であることが好ましい。
R3とR4が、それらが結合する炭素原子と共に形成する環としては、特に限定されず、脂環式環であってもよく、芳香環であってもよい。上記環としては、例えばシクロアルカン環、シクロアルケン環、アリール環、ヘテロアリール環等が挙げられ、具体的にはシクロペンタン、シクロヘキサン、シクロペンテン、シクロヘキセン、ベンゼン環、ナフタレン環、ピリジン環などが挙げられる。上記環の炭素数は特に限定されないが、3~15のものが好ましい。
R6で表される置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基又はハロゲン原子としては、例えばR1で例示したものなどが挙げられる。この場合の置換基の例として、R1について上記した置換基等が挙げられる。
R7で表される置換されていてもよいアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基としては、例えばR1で例示したものなどが挙げられる。この場合の置換基の例として、R1について上記した置換基等が挙げられる。
R2は、置換されていてもよいアリール基であることが好ましく、フェニル基又はフェニル基をハロゲン原子により置換した基であることがより好ましい。
2つのR3は、同一であることが好ましい。また、2つのR4は、同一であることが好ましい。また、R3とR4はそれらが結合する炭素原子と共に環を形成することがより好ましい。
2つのR5は、同一であることが好ましく、2つのR5がいずれも水素であることがより好ましい。
2つのR6は、同一であることが好ましく、2つのR6がいずれも水素であることがより好ましい。
式(7)
式(7)で表される化合物は、式(7-1)
で表される化合物又はその塩において、L1及びL2は、それぞれ独立して、脱離基を表す。脱離基としては、一般に脱離基として公知の基であれば特に限定されないが、例えばハロゲン原子、トシレート(OTs)、またはメシレート(OMs)等が挙げられる。
L1及びL2は、ハロゲン原子であることが好ましく、塩素原子又は臭素原子であることがより好ましい。また、L1及びL2は、同一の基であることが好ましく、いずれもハロゲン原子であることがより好ましい。
式(8)で表される化合物としては、例えば、ClCH2COCl、BrCH2COBr等が挙げられる。
式(9)で表される化合物は、式(10)
で表される化合物であることが好ましい。
式(10)で表される化合物において、R5及びR7としては、例えば式(1)で例示したものなどが挙げられる。
式(9)で表される化合物又はその塩の使用量は、反応が進行すれば特に限定されない。式(9)で表される化合物又はその塩の使用量は、具体的には、例えば式(7)で表される化合物又はその塩1モルに対し通常約0.5~5.0モルとすることができ、約0.5~2.0モルとすることが好ましい。
式(1)で表される化合物又はその塩の上記製造方法において、反応に用いる溶媒としては特に限定されないが、例えば、アルコール類(メタノール、エタノール、イソプロピルアルコール、tert-ブタノール等)、エーテル類(ジエチルエーテル、テトラヒドロフラン 、1,4-ジオキサン、1,2-ジメトキシエタン等)、ハロゲン炭化水素類(ジクロロメタン、クロロホルム、1,2-ジクロロエタン、四塩化炭素等)、芳香族炭化水素類(ベンゼン、トルエン、キシレン、ピリジン等)、脂肪族炭化水素類(ヘキサン、ペンタン、シクロヘキサン等)、ニトリル類(アセトニトリル、プロピオニトリル等)、アミド類(N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド 、N-メチルピロリドン)等の有機溶媒が挙げられ、これらの中でも、反応効率の観点から、アセトニトリル、プロピオニトリル、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン等がより好ましい。
式(1)で表される化合物又はその塩の上記製造方法において、反応に使用される塩基としては、反応に用いる塩基としては、特に限定されず、例えば、水酸化カリウム、水酸化ナトリウム、水酸化リチウム、炭酸水素ナトリウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、酢酸ナトリウム、酢酸カリウム、酢酸リチウム、安息香酸ナトリウム、安息香酸リチウム等が挙げられ、これらの中でも、反応効率の観点から、水酸化カリウム、水酸化ナトリウム、水酸化リチウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム等が好ましい。
式(1)で表される化合物又はその塩の上記製造方法において、特に限定されないが、公知の分離・精製方法により、光学的に純粋な目的物質を得ることができる。公知の分離・精製方法としては、例えば濃縮;抽出;ろ過;洗浄;結晶化;再結晶;塩酸、硫酸、メタンスルホン酸、蟻酸、トリフルオロ酢酸などのアキラルな酸との塩形成やその再結晶;キラルなマンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、10-カンファスルホン酸、リンゴ酸、光学異性体分離用カラムなどを用いた化学的光学分割;などが挙げられる。
より具体的には、式(1)で表される化合物又はその塩の上記製造方法において、光学的に純粋な目的物質を得るために、さらに分離・精製工程を実施してもよく、分離・精製方法は、特に限定されず、通常この分野で用いられる種々の方法を採用してもよい。分離方法としては、具体的には濃縮、抽出、濾過、洗浄等が挙げられ、精製法としては、具体的には、例えば、結晶化法(再結晶、又は懸濁等)、選択的溶解法、光学異性体分離用カラム等を用いた物理的光学分割等が挙げられる。前記再結晶としては、アキラルな酸(塩酸、硫酸、メタンスルホン酸、ギ酸、トリフルオロ酢酸等)との塩形成させた後に再結晶させる方法、又はキラルな酸(マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、10-カンファスルホン酸、リンゴ酸)を用いるジアステレオマー塩法等が挙げられる。
R9は置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよいアラルキル基又は置換されていてもよいヘテロアリールアルキル基を表し、Mは2価の金属カチオンを表す。)
で表される金属錯体において、R1~R6としては、例えば式(1)で例示したものなどが挙げられる。
R9で表される置換されていてもよいアラルキル基としては、例えば上記したアルキル基の水素原子をアリール基で置換したものが挙げられ、具体的にはベンジル基、フェニルエチル基、フェニルプロピル基、ナフチルメチル基などが挙げられる。
R9で表される置換されていてもよいヘテロアリールアルキル基における「ヘテロアリール基」としては、例えば窒素原子、硫黄原子および酸素原子などから選択される原子を異項原子として好ましくは1~3個含有するヘテロアリール基が挙げられ、具体的にはフラニル基、チエニル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、ピロリル基、イミダゾリル基、ピラゾリル基、ピリジル基、ピリミジニル基、ピラジニル基、フタラジニル基、トリアジニル基、インドリル基、イソインドリル基、キノリニル基、イソキノリニル基、ジベンゾフラニル基などが挙げられる。
Xが1価のアニオンの場合は、nは2を表し、Xが2価のアニオンの場合は、nは1を表す。)
で表される金属化合物を塩基の存在下で反応させ、式(3)
で表される金属錯体を得ることができる。
式(5)で表されるα-アミノ酸又はその塩としては、例えばアラニン(Ala)、アルギニン(Arg)、アスパラギン(Asn)、アスパラギン酸(Asp)、システイン(Cys)、グルタミン(Gln)、グルタミン酸(Glu)、ヒスチジン(His)、イソロイシン(Ile)、ロイシン(Leu)、リシン(Lys)、メチオニン(Met)、フェニルアラニン(Phe)、セリン(Ser)、トレオニン(Thr)、トリプトファン(Trp)、チロシン(Tyr)、バリン(Val)等のα-アミノ酸及び非天然型のα-アミノ酸とそれらの塩等が挙げられる。これらのα-アミノ酸又はその塩は、L型、D型又はそれらの任意の割合の混合物であってもよい。
で表される光学異性体又はその塩であって、反応原料である式(5)で表されるα-アミノ酸又はその塩がL型の光学異性体である場合、生成物である式(3)で表される金属錯体のα-アミノ酸由来の部分構造のキラリティは塩基性条件下で加熱することにより変換されD型となるが、反応原料である式(5)で表されるα-アミノ酸又はその塩がD型の立体配置を有する場合には、生成物である式(3)で表される金属錯体中のα-アミノ酸由来の部分構造の立体配置は変化を受けずD型のままである。
また、式(1)で表される化合物又はその塩が式(1B、R体)
また、上記製造方法において、N-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物の光学異性体を適宜選択することにより、原料として式(5)で表されるα-アミノ酸のラセミ体を用い、生成物として式(3’)で表され、R10を含むα-アミノ酸由来の部分構造の立体配置がL型又はD型のいずれか一方に変換した金属錯体を製造することもできる。
上記製造方法において、反応後に公知の分離・精製方法により、光学的に純粋な目的物質を得ることができる。そのための手段として、例えば転溶、濃縮、クロマトグラフィー、結晶化、蒸留などが挙げられる。
で表されるα-アミノ酸部分構造のキラリティが変換した金属錯体と酸を反応させ、式(3’)で表される化合物又はその塩を酸分解することにより、式(5’)
で表される所望のキラリティを有するα-アミノ酸又はその塩を製造することができる。 式(5’)で表されるα-アミノ酸又はその塩の立体配置は、式(3’)で表される金属錯体中のα-アミノ酸部分構造の立体配置と同じである。
酸の使用量は特に限定されない。酸の使用量としては、例えば式(3’)で表される金属錯体1モルに対し、通常約0.1~20モルとすることができ、約0.3~10モルとすることが好ましい。
上記製造方法において使用する溶媒はアルコールが好ましく、メタノール、エタノールを用いることがより好ましい。溶媒の使用量は、例えば式(3’)で表される金属錯体1重量部に対し通常約0.1~100倍容量、好ましくは0.5~50倍容量とすることができる。
上記製造方法において、反応時間としては、通常約0.1~72時間であればよく、約0.1~48時間であることが好ましく、約0.1~20時間であることが特に好ましい。
上記製造方法において反応を行う圧力は、特に限定されず、例えば約0.1~10気圧とすることができる。
上記製造方法において、反応後に公知の分離・精製方法により、光学的に純粋な目的物質を得ることができる。
上記製造方法により、式(5’)
で表される任意のキラリティを有するα-アミノ酸又はその塩を製造することができる。 式(5’)で表されるα-アミノ酸としては、例えば上記式(5)にて例示したもの等が挙げられる。但し、(5’)で表されるα-アミノ酸又はその塩のα炭素における立体配置が式(5)で表されるα-アミノ酸又はその塩から変換されている。
実施例及び参考例において、以下のHPLC条件で測定した。
<HPLC条件-1:錯体分析条件>
Column: InertsilTM ODS-3 (3 μm, 150 x 4.6 mm i.d.)
Eluent: A: B = 40:60 to 20:80 (0 to 25 min)
20:80 (25 min to 45 min)
A = 10mM ギ酸アンモニウム 0.1% ギ酸緩衝液
B = アセトニトリル
Flow rate: 1.0 mL/min
Temp: 40℃
Detector: UV 254 nm
Column: CHIRALCELL OJ-RH (5 μm, 150 x 4.6 mm i.d.)
Eluent: A: B = 65:35 (0 to 30 min)
A = 0.1% リン酸水溶液
B = 0.1% リン酸含有アセトニトリル
Flow rate: 0.5 mL/min
Temp: 35℃
Detector: UV 200 nm
Column: CHIRALCELL OJ-RH (5 μm, 150 x 4.6 mm i.d.)
Eluent: A: B = 65: 35 (0 to 30 min)
A = 0.1% リン酸水溶液
B = 0.1% リン酸含有アセトニトリル
Flow rate: 0.5 mL/min
Temp: 35℃
Detector: UV 254 nm
Column: InertsilTM ODS-3 (3 μm, 150 x 4.6 mm i.d.)
Eluent: A: B = 40:60 (0 to 40 min)及び10:90 (41 min to 50 min)
A = 10 mM ギ酸アンモニウム 0.1% ギ酸緩衝液
B = アセトニトリル
Flow rate: 0.5 mL/min
Temp: 40℃
Detector: UV 254 nm
Column: CHIRALPAK AS-RH (5 μm, 150 x 4.6 mm i.d.)
Eluent: A: B = 60: 40 (0 to 12 min)
A = リン酸水溶液(pH = 2)
B = アセトニトリル
Flow rate: 1.0 mL/min
Temp: 25℃
Detector: UV 200 nm
実施例1-1: (S)-N-(2-ベンゾイルフェニル)-2-[3,5-ジヒドロ-4H-ジナフト[2,1-c:1’,2’-e]アゼピン-4-イル]アセトアミドの合成
1H-NMR (200 MHz, CDCl3): δ 3.10 and 3.57 (1H each, ABq, J = 16.7 Hz, COCH2), 3.40 and 3.66 (2H each, ABq, J = 12.3 Hz, 2 x NCH2), 7.13 (1H, ddd, J = 7.9, 7.3, 1.1 Hz, ArH), 7.26 (1H, ddd, J = 8.8, 6.4, 1.3 Hz, ArH), 7.42-7.63 (12H, m, ArH), 7.74-7.80 (2H, m, ArH), 7.92-7.98 (2H, m, ArH), 7.94 (2H, d, J = 8.2 Hz, ArH), 8.64 (1H, dd, J = 8.4, 0.7 Hz, ArH), 11.59 (1H, br s, NH).
13C-NMR (50.3 MHz, CDCl3): δ 56.4 (CH2), 60.5 (CH2), 122.0 (ArCH), 122.5 (ArCH), 125.6 (ArCH), 125.8 (ArCH), 127.5 (ArCH), 127.7 (ArCH), 128.3 (ArCH), 128.6 (ArCH), 130.2 (ArCH), 131.5 (quaternary ArC), 132.5 (ArCH), 132.6 (ArCH), 133.2 (quaternary ArC), 133.3 (quaternary ArC), 133.4 (ArCH), 135.0 (quaternary ArC), 138.5 (quaternary ArC), 139.0 (quaternary ArC), 170.2 (CO), 197.8 (CO).
1H-NMR (200 MHz, CDCl3): δ 4.02 (2H, s, COCH2), 7.48-7.76 (7H, m, ArH), 8.55-8.60 (1H, m, ArH), 11.32 (1H, br s, NH).
N-(2-ベンゾイル-4-クロロフェニル)-2-ブロモアセトアミド (2.0 g, 5.7 mmol)のアセトニトリル溶液(60 mL)に炭酸カリウム(1.18 g, 8.5 mmol)と(S)-ビナフチルアミンを添加して、40℃に加熱し、16時間撹拌した。反応終了後、反応懸濁液を濃縮乾固した。濃縮残渣をシリカゲルクロマトグラフィー(n-ヘキサン:酢酸エチル=4:1 (v/v))にて精製し、(S)-N-(2-ベンゾイル-4-クロロフェニル)-2-[3,5-ジヒドロ-4H-ジナフト[2,1-c:1’,2’-e]アゼピン-4-イル]アセトアミド(3.25 g, 収率 定量的, 純度99.7%, 99.8% ee)を淡黄色結晶として得た。
1H-NMR (200 MHz, CDCl3): δ 3.09 and 3.54 (1H each, ABq, J = 16.8 Hz, COCH2), 3.39 and 3.61 (2H each, ABq, J = 12.1 Hz, 2 x NCH2), 7.21-7.30 (2H, m, ArH), 7.42-7.65 (11H, m, ArH), 7.73-7.80 (2H, m, ArH), 7.92-7.98 (2H, m, ArH), 7.94 (2H, d, J = 8.2 Hz, ArH), 8.62 (2H, d, J = 8.6 Hz, ArH), 11.49 (1H, br s, NH).
13C-NMR (50.3 MHz, CDCl3): δ 56.4 (CH2), 60.3 (CH2), 123.3 (ArCH), 125.6 (ArCH), 125.9 (ArCH), 126.8 (quaternary ArC), 127.5 (ArCH), 127.6 (ArCH), 127.8 (quaternary ArC), 127.9 (quaternary ArC), 128.3 (ArCH), 128.6 (ArCH), 128.7 (ArCH), 130.2 (ArCH), 131.4 (quaternary ArC), 131.6 (ArCH), 133.1 (ArCH), 133.3 (quaternary ArC), 135.0 (quaternary ArC), 137.4 (quaternary ArC), 137.6 (quaternary ArC), 170.2 (CO), 196.4 (CO).
実施例2-1:L-フェニルアラニンのキラル反転反応によるD-フェニルアラニンの合成:D-フェニルアラニンを部分構造に持つNi錯体の合成
1H-NMR (200 MHz, CDCl3):δ 0.43 (3H, d, J = 6.4 Hz, Me), 0.87 (3H, d, J = 6.6 Hz, Me), 1.28 (1H, ddd, J = 13.3, 10.1, 3.7 Hz, one of β-CH2 of Leu part), 1.88-2.05 (1H, m, CHMe2), 2.34 (1H, ddd, J = 13.3, 10.5, 3.5 Hz, one of β-CH2 of Leu part), 2.72 [1H, d, J = 12.1 Hz, one of azepine C(α)H2N], 3.07 [1H, d, J = 15.6 Hz, one of azepine C(α) H2N], 3.67 and 3.73 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH2), 3.81 (1H, dd, J = 10.1, 3.5 Hz, α-H of Leu part), 4.56 [1H, d, J = 15.6 Hz, one of azepine C(α’)H2N], 4.83 [1H, d, J = 12.1 Hz, one of azepine C(α) H2N], 6.66 (1H, d, J = 2.4 Hz, ArH), 6.89-6.97 (1H, m, ArH), 7.18-7.58 (12H, m, ArH), 7.94-8.03 (3H, m, ArH), 8.16 (1H, d, J = 8.2 Hz, ArH), 8.42 (1H, d, J = 9.2 Hz, ArH), 8.77 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 20.8 and 23.8 (2 x Me of Leu part), 24.3 (γ-CH of Leu part), 45.4 (β-CH2 of Leu part), 58.8 (NCOCH2), 61.9 and 66.4 (2 x CH2 of azepine), 69.4 (α-CH of Leu part), 125.1 (ArCH), 126.1 (quaternary ArC), 126.37 (ArCH), 126.44 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.8 (ArCH), 127.9 (ArCH), 128.4 (ArCH), 128.66 (ArCH), 128.73 (quaternary ArC), 129.17 (ArCH), 129.24 (ArCH), 129.5 (ArCH), 130.3 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.5 (quaternary ArC), 132.4 (ArCH), 132.5 (ArCH), 132.8 (quaternary ArC), 133.7 (quaternary ArC), 134.1 (quaternary ArC), 135.6 (quaternary ArC), 136.0 (quaternary ArC), 140.9 (quaternary ArC), 169.5, 174.6, 178.5 (CN and 2 x CO).
1H-NMR (200 MHz, CDCl3): δ 1.82-2.15 (2H, m, β-CH2 of Met part), 2.12 (3H, s, SMe), 2.70 [1H, d, J = 12.3 Hz, one of azepine C(α) H2N], 2.76 (1H, dt, J = 13.4, 7.0 Hz, one of γ-CH2 of Met part), 3.05 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.24 (1H, ddd, J = 13.4, 8.1, 6.3 Hz, one of γ-CH2 of Met part), 3.67 and 3.74 (1H each, ABq, J = 14.0 Hz, acetanilide NCOCH2), 3.97 (1H, dd, J = 6.8, 4.0 Hz, α-H of Met part), 4.55 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 4.84 [1H, d, J = 12.3 Hz, one of azepine C(α) H2N], 6.64 (1H, d, J = 2.4 Hz, ArH), 6.90-6.98 (1H, m, ArH), 7.12-7.19 (1H, m, ArH), 7.22-7.59 (11H, m, ArH), 7.95-8.03 (3H, m, ArH), 8.16 (1H, d, J = 8.2 Hz, ArH), 8.43 (1H, d, J = 9.2 Hz, ArH), 8.80 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 15.7 (Me), 29.8 (CH2), 33.2 (CH2), 58.7 (NCOCH2), 61.8 and 66.5 (2 x CH2 of azepine), 69.8 (α-CH of Glu part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.37 (quaternary ArC), 126.44 (ArCH), 126.9 (ArCH), 127.3 (ArCH), 127.5 (ArCH), 127.9 (ArCH), 128.4 (ArCH), 128.6 (ArCH), 128.7 (quaternary ArC), 129.2 (ArCH), 129.37 (ArCH), 129.42 (ArCH), 130.4 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.5 (quaternary ArC), 132.4 (ArCH), 132.7 (ArCH), 132.9 (quaternary ArC), 133.7 (quaternary ArC), 134.0 (quaternary ArC), 135.5 (quaternary ArC), 136.0 (quaternary ArC), 141.2 (quaternary ArC), 170.2, 174.6, 178.0 (CN and 2 x CO).
1H-NMR (200 MHz, CDCl3): δ 1.52 (1H, d, J = 14.1 Hz, one of acetanilide NCOCH2), 2.25 [1H, d, J = 12.1 Hz, one of azepine C(α)H2N], 2.34 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 2.74 (1H, HA of ABX type, JAB = 14.4 Hz, JAX = 5.7 Hz, one of AA β-CH2), 2.81 (1H, d, J = 14.1 Hz, one of acetanilide NCOCH2), 3.04 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.30 (1H, HB of ABX type, JAB = 14.4 Hz, JBX = 2.2 Hz, one of AA β-CH2), 4.16 (1H, HX of ABX type, JAX = 5.7 Hz, JBX = 2.2 Hz, α-H of AA part), 4.43 [1H, d, J = 12.1 Hz, one of azepine C(α) H2N], 6.68 (1H, d, J = 2.6 Hz, ArH), 6.99 (1H, d, J = 2.2 Hz, ArH), 7.02-7.63 (15H, m, ArH), 7.74-7.81 (2H, m, ArH), 7.85-7.94 (3H, m, ArH), 8.06 (1H, d, J = 8.4 Hz, ArH), 8.26 (1H, d, J = 9.0 Hz, ArH), 8.66 (1H, d, J = 8.2 Hz, ArH), 9.11 (1H, br d, J = 1.8 Hz, NH).
13C-NMR (50.3 MHz, CDCl3): δ 29.7 (β-CH2 of Phe part), 56.5 (NCOCH2), 61.4 and 65.0 (2 x CH2 of azepine), 71.8 (α-CH of AA part), 110.4 (ArCH), 111.2 (ArCH), 120.7 (ArCH), 121.1 (ArCH), 122.9 (ArCH), 125.2 (ArCH), 125.5 (ArCH), 126.1 (quaternary ArC), 126.2 (ArCH), 126.3 (ArCH), 127.1 (ArCH), 127.2 (ArCH), 127.4 (ArCH), 127.7 (ArCH), 128.3 (ArCH), 128.4 (ArCH), 128.7 (ArCH), 128.9 (quaternary ArC), 129.0 (quaternary ArC), 129.1 (ArCH), 129.4 (ArCH), 130.4 (ArCH), 130.9 (quaternary ArC), 131.0 (quaternary ArC), 131.3 (quaternary ArC), 132.3 (ArCH), 132.4 (ArCH), 132.8 (quaternary ArC), 133.4 (quaternary ArC), 133.9 (quaternary ArC), 135.2 (quaternary ArC), 135.8 (quaternary ArC), 136.8 (quaternary ArC), 141.0 (quaternary ArC), 169.2, 174.6, 178.8 (CN and 2 x CO).
1H-NMR (200 MHz, CDCl3): δ 1.68-1.88 (1H, m), 2.09-2.25 (1H, m), 2.34-2.70 (2H, m), 2.72 [1H, d, J = 12.2 Hz, one of azepine C(α) H2N], 3.00 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.62 and 3.73 (1H each, ABq, J = 13.7 Hz, acetanilide NCOCH2), 3.79 (1H, dd, J = 8.7, 4.3 Hz, α-H of Gln part), 4.56 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 4.84 [1H, d, J = 12.2 Hz, one of azepine C(α) H2N], 5.20 (1H, br s, one of CONH2), 6.38 (1H, br s, one of CONH2), 6.66 (1H, d, J = 2.4 Hz, ArH), 6.94-7.01 (1H, m, ArH), 7.13-7.20 (1H, m, ArH), 7.21-7.33 (3H, m, ArH), 7.37-7.59 (8H, m, ArH), 7.86-8.01 (3H, m, ArH), 8.15 (1H, d, J = 8.2 Hz, ArH), 8.45 (1H, d, J = 9.2 Hz, ArH), 8.74 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 30.2 (CH2), 31.2 (CH2), 58.4 (NCOCH2), 61.9 and 66.2 (2 x CH2 of azepine), 69.8 (α-CH of Gln part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.5 (ArCH), 126.6 (ArCH), 127.3 (ArCH), 127.5 (ArCH), 127.8 (ArCH), 128.0 (ArCH), 128.1 (quaternary ArC), 128.4 (ArCH), 128.6 (ArCH), 128.8 (quaternary ArC), 129.0 (ArCH), 129.1 (ArCH), 129.3 (ArCH), 129.5 (ArCH), 130.3 (ArCH), 131.1 (quaternary ArC), 131.2 (quaternary ArC), 131.4 (quaternary ArC), 132.6 (ArCH), 132.7 (ArCH), 133.6 (quaternary ArC), 133.9 (quaternary ArC), 135.5 (quaternary ArC), 136.1 (quaternary ArC), 141.0 (quaternary ArC), 170.7, 173.6, 174.8, 178.5 (CN and 3 x CO).
1H-NMR (200 MHz, CDCl3): δ 1.60-1.78 (1H, m, one of β-CH2 of Glu part), 1.90-2.10 (1H, m, one of β-CH2 of Glu part), 2.50-2.70 (1H, m, one of γ-CH2 of Glu part), 2.64 [1H, d, J = 12.1 Hz, one of azepine C(α) H2N], 2.95 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.20-3.41 (1H, m, one of γ-CH2 of Glu part), 3.67 and 3.81 (1H each, ABq, J = 13.8 Hz, acetanilide NCOCH2), 3.94 (1H, br t-like, α-H of Glu part), 4.5-5.1 (1H, br, CO2H), 4.77 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 4.78 [1H, d, J = 12.1 Hz, one of azepine C(α) H2N], 6.58 (1H, d, J = 2.6 Hz, ArH), 6.98-7.64 (12H, m, ArH), 7.61 (1H, d, J = 8.2 Hz, ArH), 7.91-8.01 (3H, m, ArH), 8.14 (1H, d, J = 8.4 Hz, ArH), 8.28 (1H, d, J = 9.2 Hz, ArH), 8.78 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 27.4 (CH2), 30.4 (CH2), 58.5 (NCOCH2), 61.8 and 66.5 (2 x CH2 of azepine), 70.4 (α-CH of Glu part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.37 (ArCH), 126.44 (ArCH), 126.6 (ArCH), 127.5 (ArCH), 127.6 (ArCH), 127.8 (ArCH), 128.0 (ArCH), 128.37 (quaternary ArC), 128.44 (ArCH), 128.7 (ArCH), 129.0 (ArCH), 129.1 (ArCH), 129.2 (ArCH), 129.4 (ArCH), 130.2 (ArCH), 131.1 (quaternary ArC), 131.2 (quaternary ArC), 131.5 (quaternary ArC), 132.5 (ArCH), 132.9 (quaternary ArC), 133.7 (quaternary ArC), 134.0 (quaternary ArC), 135.4 (quaternary ArC), 136.1 (quaternary ArC), 140.8 (quaternary ArC), 171.5, 175.7, 176.2, 178.3 (CN and 3 x CO).
1H-NMR (200 MHz, CDCl3): δ 1.20-1.80 (4H, m), 1.82-2.02 (1H, m), 2.23-2.43 (1H, m), 2.52-2.78 (1H, br), 2.72 [1H, d, J = 12.3 Hz, one of azepine C(α) H2N], 3.04 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.27 (3H, br, NH2 and one of CH2), 3.66 and 3.83 (1H each, ABq, J = 13.6 Hz, acetanilide NCOCH2), 3.82 (1H, HX of ABX system, overlapped, α-H of Lys part), 4.73 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 4.80 [1H, d, J = 12.3 Hz, one of azepine C(α) H2N], 6.64 (1H, d, J = 2.6 Hz, ArH), 6.84-6.91 (1H, m, ArH), 7.14-7.56 (11H, m, ArH), 7.61 (1H, d, J = 8.2 Hz, ArH), 7.90-8.00 (3H, m, ArH), 8.14 (1H, d, J = 8.2 Hz, ArH), 8.42 (1H, d, J = 9.2 Hz, ArH), 8.75 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 22.6 (γ-CH2), 30.9 (δ-CH2), 34.6 (β-CH2), 40.6 (ε-CH2), 58.5 (NCOCH2), 61.8 and 66.3 (2 x CH2 of azepine), 70.6 (α-CH of Lys part), 125.2 (ArCH), 126.2 (quaternary ArC), 126.3 (quaternary ArC), 126.4 (ArCH), 127.0 (ArCH), 127.5 (ArCH), 127.9 (ArCH), 128.4 (ArCH), 128.7 (ArCH), 128.9 (quaternary ArC), 129.17 (ArCH), 129.24 (ArCH), 129.4 (ArCH), 130.3 (ArCH), 131.1 (quaternary ArC), 131.2 (quaternary ArC), 131.4 (quaternary ArC), 132.4 (ArCH), 132.6 (ArCH), 132.8 (quaternary ArC), 133.7 (quaternary ArC), 134.0 (quaternary ArC), 135.5 (quaternary ArC), 136.0 (quaternary ArC), 141.0 (quaternary ArC), 170.0, 174.8, 178.5 (CN and 2 x CO).
アンモニア水層及び水層抽出液を合わせて濃縮乾固させた後、得られた固体を9%アンモニア水(3 mL)に溶解して陽イオン交換樹脂カラム(三菱化学社製、商品名 [SK-1B], 9mL, 溶離液:水、続いてアンモニア水 (2% → 8%))に通すと、フェニルアラニン(0.083 g, 粗生成物)を得た。
フェニルアラニン(0.078 g)に炭酸水素ナトリウム(0.041 mg, 1 eq.)-炭酸ナトリウム(0.103 mg, 2 eq.)水溶液(3 mL)、アセトン(1 mL)を加えて溶解し、氷浴中N-ベンジルオキシカルボニルオキシコハク酸イミド(0.121 g, 1 eq.)のアセトン溶液(1 mL)を加えて室温にて3時間撹拌した。反応液を濃縮した残留物を酢酸エチル(18 mL)及び1N塩酸(2.5 mL)を加えて分層した後、水層を酢酸エチル(18 mL)で抽出した。有機層を飽和食塩水(5 mL, 2回)で洗浄し、硫酸ナトリウムで乾燥後、濃縮して黄色油状物質(0.182 g)を得た。得られた黄色油状物質をイソプロピルコール(0.08 mL)-酢酸エチル(0.8 mL)に溶解し、ジシクロヘキシルアミン(0.094 g, 1 eq.) の酢酸エチル溶液(0.4 mL)、さらに酢酸エチル(2.0 mL)を加えて室温にて9時間撹拌した。析出した結晶をろ取し,50℃で送風乾燥して、Z-L-フェニルアラニン・DCHA塩(0.178 g, 収率76%,99.0% ee)を白色結晶として得た。
一方、水層抽出液(12mL)を濃縮乾固した後、得られた固体を13%アンモニア水(4 mL)に溶解して陽イオン交換樹脂カラム(三菱化学社製、商品名 [SK-1B], 30mL, 溶離液:水、続いてアンモニア水 (8%))に通すと、フェニルアラニン(0.102 g, 粗生成物, 定量的)を得た。
フェニルアラニン(0.102 g)に炭酸水素ナトリウム(0.090 mg, 2 eq.)-炭酸ナトリウム(0.057 mg, 1 eq.)水溶液(3 mL)、アセトン(1 mL)を加えて溶解し、氷浴中N-ベンジルオキシカルボニルオキシコハク酸イミド(0.139 g, 1.04 eq.)のアセトン溶液(2 mL)を加えて室温にて3.5時間撹拌した。反応液を濃縮した残留物に水(17 mL)及びトルエン(1 mL)を加えて分層した後、水層に10%クエン酸水溶液を加えてpH=3に調整し、酢酸エチル(30 mL, 15 mL)で抽出した。有機層を水(2 mL)及び飽和食塩水(2 mL, 3回)で洗浄し、硫酸ナトリウムで乾燥後、濃縮して黄色油状物質(0.161g、租生成物, 定量的)を得た。
得られた黄色油状物質をイソプロピルアルコール(0.01 mL)-酢酸エチル(0.6 mL)に溶解し、ジシクロヘキシルアミン(0.097 g, 1 eq.) の酢酸エチル溶液(0.1 mL)を添加後、さらに酢酸エチル(0.9mL)及びヘキサン(3 mL)を加えて室温にて終夜撹拌した。析出した結晶をろ取し,50℃で真空乾燥して、Z-D-フェニルアラニン・DCHA塩(0.247 g, 収率96%,99.0% ee、Z-Pheと略記する。)を白色結晶として得た。
一方、水層抽出液(20 mL)を少量の塩化メチレンで洗浄した後、濃縮乾固して得られた固体を水-メタノールおよび少量のアンモニア水(1 mL)に溶解して陽イオン交換樹脂カラム(三菱化学社製、商品名 [SK-1B], 3 mL, 溶離液:水、続いてアンモニア水 (8%))に通すと、D-リシン(0.038 g, 粗生成物)を得た。
D-リシン(0.034 g)に炭酸水素ナトリウム(0.079 mg, 4 eq.)-炭酸ナトリウム(0.050 mg, 2 eq.)水溶液(1 mL)、THF(1 mL)を加えて溶解し、氷浴中N-ベンジルオキシカルボニルオキシコハク酸イミド(0.118 g, 2 eq.)のTHF溶液(2.5 mL)を加えて室温にて2時間撹拌した。反応液を濃縮して得られた残留物に水(10 mL)及びトルエン(1 mL)を加えて分取した後、水層に10%クエン酸水溶液を加えpH=3に調整し、酢酸エチル(15 mL, 10 mL, 5 mL)で抽出した。有機層を水(2 mL, 2回)及び飽和食塩水(5 mL, 2回)で洗浄し、硫酸ナトリウムで乾燥した。硫酸ナトリウムをろ去後、濃縮して得られた黄色油状物質(0.102 g, 粗生成物, 収率93%)をシリカゲルカラムクロマトグラフィーにて精製すると、Z基で保護されたD-リシン(Z-D-Lys(Z))(0.082 g)を油状物質として得た。この無色油状物質(0.064 g)をイソプロピルアルコール(0.01 mL)-酢酸エチル(0.6 mL)に溶解し、ジシクロヘキシルアミン(0.028 g, 1 eq.)の酢酸エチル溶液(0.1 mL)、ならびに酢酸エチル(0.9 mL)およびヘキサン(3 mL)を加えて室温にて終夜撹拌した。析出した結晶をろ取し、50℃で真空乾燥して、Z-D-Lys(Z)・DCHA塩 (0.084g, 収率69%(Ni(II)錯体からの収率),93.2% ee)を白色結晶として得た。
1H-NMR (200 MHz, CDCl3): δ 2.42 [1H, d, J = 12.3 Hz, one of azepine C(α)H2N], 2.59 (1H, HA of ABX type, JAB = 13.6 Hz, JAX = 5.3 Hz, one of Phe β-CH2), 2.61 [1H, d, J = 15.5 Hz, one of azepine C(α')H2N], 2.76 and 3.18 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH2), 3.00 (1H, HB of ABX type, JAB = 13.6 Hz, JBX = 3.0 Hz, one of Pheβ-CH2), 3.68 [1H, d, J = 15.5 Hz, one of azepine C(α’)H2N], 4.22 (1H, HX of ABX type, JAX = 5.3 Hz, JBX = 3.0 Hz, α-H of Phe part), 4.54 [1H, d, J = 12.3 Hz, one of azepine C(α)H2N], 6.67 (1H, d, J = 2.4 Hz), 7.05-7.64 (15H, m, ArH), 7.66-7.85 (3H, m, ArH), 7.90-7.99 (3H, m, ArH), 8.09 (1H, d, J = 8.2 Hz, ArH), 8.35 (1H, d, J = 9.2 Hz, ArH), 8.67 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 39.1 (β-CH2 of Phe part), 57.6 (NCOCH2), 61.6 and 65.9 (2 x CH2 of azepine), 72.1 (α-CH of Phe part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.3 (ArCH), 127.1 (ArCH), 127.5 (ArCH), 127.6 (ArCH), 127.7 (ArCH), 127.8 (ArCH), 128.4 (ArCH), 128.6 (ArCH), 128.8 (quaternary ArC), 128.95 (ArCH), 129.02 (ArCH), 129.3 (ArCH), 129.4 (ArCH), 130.4 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.5 (quaternary ArC), 131.8 (ArCH), 132.4 (ArCH), 132.7 (ArCH), 133.0 (quaternary ArC), 133.6 (quaternary ArC), 134.0 (quaternary ArC), 135.4 (quaternary ArC), 135.9 (quaternary ArC), 136.5 (quaternary ArC), 141.4 (quaternary ArC), 169.9, 174.3, 177.4 (CN and 2 x CO).
1H-NMR (200 MHz, CDCl3): δ 2.42 [1H, d, J = 12.1 Hz, one of azepine C(α)H2N], 2.59 (1H, HA of ABX type, JAB = 13.6 Hz, JAX = 5.5 Hz, one of Pheβ-CH2), 2.61 [1H, d, J = 15.6 Hz, one of azepine C(α’)H2N], 2.76 and 3.17 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH2), 3.00 (1H, HB of ABX type, JAB = 13.6 Hz, JBX = 3.0 Hz, one of Phe β-CH2), 3.68 [1H, d, J = 15.6 Hz, one of azepine C(α’)H2N], 4.23 (1H, HX of ABX type, JAX = 5.5 Hz, JBX = 3.0 Hz, α-H of Phe part), 4.54 [1H, d, J = 12.1 Hz, one of azepine C(α)H2N], 6.67 (1H, d, J = 2.4 Hz), 7.05-8.02 (21H, m, ArH), 8.09 (1H, d, J = 8.4 Hz, ArH), 8.34 (1H, d, J = 9.2 Hz, ArH), 8.68 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ39.0 (β-CH2 of Phe part), 57.5 (NCOCH2), 61.6 and 65.9 (2 x CH2 of azepine), 72.1 (α-CH of Phe part), 125.2 (ArCH), 126.1 (quaternary ArC), 126.4 (ArCH), 127.1 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.7 (ArCH), 127.8 (ArCH), 128.4 (ArCH), 128.6 (ArCH), 128.8 (quaternary ArC), 129.0 (ArCH), 129.1 (ArCH), 129.3 (ArCH), 129.4 (ArCH), 130.5 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.4 (quaternary ArC), 131.8 (ArCH), 132.4 (ArCH), 132.7 (ArCH), 132.9 (quaternary ArC), 133.6 (quaternary ArC), 133.9 (quaternary ArC), 135.3 (quaternary ArC), 135.9 (quaternary ArC), 136.5 (quaternary ArC), 141.4 (quaternary ArC), 169.9, 174.3, 177.4 (CN and 2 x CO).
1H-NMR (200 MHz, CDCl3): δ0.80 (3H, d, J = 7.0 Hz, Me), 1.79 (1H, doubtet of septets, J = 3.5, 7.0 Hz, CHMe2), 2.18 (3H, d, J = 6.8 Hz, Me), 2.54 [1H, d, J = 12.3 Hz, one of azepine C(α)H2N], 3.02 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.64 and 3.75 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH2), 3.72 (1H, d, J = 3.3 Hz, α-H of Val part), 4.54 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 4.73 [1H, d, J = 12.3 Hz, one of azepine C(α)H2N], 6.55 (1H, d, J = 2.4 Hz), 6.84-6.95 (2H, m, ArH), 7.14-7.55 (10H, m, ArH), 7.55 (1H, d, J = 8.4 Hz, ArH), 7.92-8.04 (3H, m, ArH), 8.19 (1H, d, J = 8.2 Hz, ArH), 8.44 (1H, d, J = 9.0 Hz, ArH), 8.99 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ18.5 and 19.7 (2 x Me of Val part), 34.5 (β-CH of Val part), 59.1 (NCOCH2), 61.5 and 66.7 (2 x CH2 of azepine), 75.9 (α-CH of Val part), 125.0 (ArCH), 126.1 (quaternary ArC), 126.37 (ArCH), 126.44 (ArCH), 127.1 (ArCH), 127.2 (ArCH), 127.4 (ArCH), 127.8 (ArCH), 128.0 (ArCH), 128.4 (ArCH), 128.55 (quaternary ArC), 128.62 (quaternary ArC), 128.7 (ArCH), 128.9 (ArCH), 129.1 (ArCH), 129.5 (ArCH), 130.1 (ArCH), 131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.5 (quaternary ArC), 132.4 (ArCH), 132.5 (ArCH), 132.7 (quaternary ArC), 133.7 (quaternary ArC), 134.1 (quaternary ArC), 135.4 (quaternary ArC), 136.0 (quaternary ArC), 141.0 (quaternary ArC), 169.7, 174.3, 176.3 (CN and 2 x CO).
ESI-MS (positive mode): m/z = 694.1 for [M + H]+.
1H-NMR (200 MHz, CDCl3): δ1.51 (3H, d, J = 7.0 Hz, Me), 2.73 [1H, d, J = 12.2 Hz, one of azepine C(α)H2N], 3.08 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 3.68 and 3.76 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH2), 3.84 (1H, q, J = 7.0 Hz, α-H of Ala part), 4.57 [1H, d, J = 15.6 Hz, one of azepine C(α')H2N], 4.84 [1H, d, J = 12.1 Hz, one of azepine C(α)H2N], 6.66 (1H, d, J = 2.6 Hz), 6.91-6.99 (1H, m, ArH), 7.16-7.32 (4H, m, ArH), 7.35-7.41 (1H, m, ArH), 7.43-7.57 (7H, m, ArH), 7.94-8.03 (3H, m, ArH), 8.16 (1H, d, J = 8.3 Hz, ArH), 8.44 (1H, d, J = 9.2 Hz, ArH), 8.76 (1H, d, J = 8.3 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ 21.5 (Me of Ala part), 58.7 (NCOCH2), 61.9 and 66.3 (2 x CH2 of azepine), 66.9 (α-CH of Ala part), 125.1 (ArCH), 126.1 (quaternary ArC), 126.37 (quaternary ArC), 126.44 (ArCH), 126.9 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.6 (ArCH), 127.8 (ArCH), 128.2 (quaternary ArC), 128.4 (ArCH), 128.7 (ArCH), 129.2 (ArCH), 129.5 (ArCH), 130.2 (ArCH), 131.0 (quaternary ArC), 131.3 (quaternary ArC), 131.5 (quaternary ArC), 132.4 (ArCH), 132.6 (ArCH), 132.7 (quaternary ArC), 133.7 (quaternary ArC), 134.1 (quaternary ArC), 135.6 (quaternary ArC), 136.0 (quaternary ArC), 140.9 (quaternary ArC), 170.2, 174.6, 179.7 (CN and 2 x CO).
結果を図18に示す。
この錯体を実施例3-1と同様の方法で処理することによりL-アラニンを得ることができる。
1H-NMR (200 MHz, CDCl3): δ 2.44 [1H, d, J = 12.1 Hz, one of azepine C(α) H2N], 2.49 (1H, HA of ABX type, JAB = 13.9 Hz, JAX = 4.9 Hz, one of Tyr β-CH2), 2.71 [1H, d, J = 15.7 Hz, one of azepine C(α')H2N], 2.92 (1H, HB of ABX type, JAB = 13.9 Hz, JBX = 2.7 Hz, one of Tyr β-CH2), 2.99 and 3.19 (1H each, ABq, J = 13.9 Hz, acetanilide NCOCH2), 3.92 [1H, d, J = 15.7 Hz, one of azepine C(α')H2N], 4.18 (1H, HX of ABX type, JAX = 4.9 Hz, JBX = 2.7 Hz, α-H of Tyr part), 4.59 [1H, d, J = 12.1 Hz, one of azepine C(α) H2N], 6.67 (1H, d, J = 2.6 Hz), 6.93-7.00 (1H, m, ArH), 7.09-7.62 (16H, m, ArH), 7.77 (1H, d, J = 7.9 Hz, ArH), 7.81 (1H, d, J = 7.7 Hz, ArH), 7.92 (1H, d, J = 8.2 Hz, ArH), 8.09 (1H, d, J = 8.2 Hz, ArH), 8.32 (1H, d, J = 9.0 Hz, ArH), 8.56 (1H, br, OH), 8.70 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ38.3 (β-CH2 of Tyr part), 57.6 (NCOCH2), 61.8 and 65.8 (2 x CH2 of azepine), 72.4 (α-CH of Tyr part), 125.3 (ArCH), 126.3 (ArCH), 126.4 (ArCH), 126.5 (quaternary ArC), 126.9 (quaternary ArC), 127.1 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.7 (ArCH), 128.4 (ArCH), 128.55 (ArCH), 128.59 (quaternary ArC), 128.8 (quaternary ArC), 129.1 (ArCH), 129.4 (ArCH), 130.5 (ArCH), 130.9 (quaternary ArC), 131.1 (quaternary ArC), 131.3 (quaternary ArC), 132.5 (ArCH), 132.6 (ArCH), 132.7 (quaternary ArC), 133.5 (quaternary ArC), 133.9 (quaternary ArC), 135.2 (quaternary ArC), 136.0 (quaternary ArC), 140.7 (quaternary ArC), 157.0 (quaternary ArC), 169.9, 174.9, 177.9 (CN and 2 x CO).
Claims (8)
- 式(1)
R2は水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R3、R4は、それぞれ独立して、水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又はハロゲン原子を表し、
2つのR3は同一であっても異なっていてもよく、
2つのR4は同一であっても異なっていてもよく、
R3とR4はそれらが結合する炭素原子と共に環を形成してもよく、
R5は、水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、カルボキシル基、ハロゲン原子、―COOR7又は-C(OH)(R7)2を表し、
2つのR5は同一であっても異なっていてもよく、
R6は、水素、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基又はハロゲン原子を表し、
2つのR6は同一であっても異なっていてもよく、
2つのR6はそれらが結合する炭素原子と共に環を形成してもよく、
R7は水素、置換されていてもよいアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表す。*は不斉軸を表す。)
で表されるN-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物又はその塩。 - R1が水素、塩素、メチル基又はニトロ基であり、
R5及びR6がいずれも水素である請求項2に記載の化合物。 - 式(3)
R2は水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R3、R4は、それぞれ独立して、水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又はハロゲン原子を表し、
2つのR3は同一であっても異なっていてもよく、
2つのR4は同一であっても異なっていてもよく、
R3とR4はそれらが結合する炭素原子と共に環を形成してもよく、
R5は、水素、置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいアルコキシ基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、カルボキシル基、ハロゲン原子、―COOR7又は-C(OH)(R7)2を表し、
2つのR5は同一であっても異なっていてもよく、
R6は、水素、置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基又はハロゲン原子を表し、
2つのR6は同一であっても異なっていてもよく、
2つのR6はそれらが結合する炭素原子と共に環を形成してもよく、
R7は水素、置換されていてもよいアルキル基、置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を表し、
R9は置換されていてもよいアルキル基、置換されていてもよいアルキニル基、置換されていてもよいアルケニル基、置換されていてもよいシクロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよいアラルキル基又は置換されていてもよいヘテロアリールアルキル基を表し、*は不斉軸を表す。Mは2価の金属カチオンを表す。)
で表される金属錯体。 - R1が水素、塩素、メチル基又はニトロ基であり、
二組のR3とR4のいずれの組においてもR3とR4が結合しているベンゼン環の炭素原子と共に芳香環または脂環式構造を形成し、
R5及びR6がいずれも水素であり、Mがニッケル、銅、パラジウム、白金カチオンである請求項4又は5に記載の金属錯体。 - α―アミノ酸の立体配置を変換させる方法であって、選択されたRまたはS体の光学活性である請求項1に記載の式(1)で表されるN-(2-アシルアリール)-2-[5,7-ジヒドロ-6H-ジベンゾ[c,e]アゼピン-6-イル]アセトアミド化合物又はその塩とα-アミノ酸より生じたイミン化合物の請求項4に記載の式(3)で表される二価金属カチオン金属錯体を、塩基性条件下で加熱することで、α-アミノ酸部分構造のα炭素の立体配置を変換させ、その後に金属錯体を酸分解してα-アミノ酸を遊離させることにより純粋なα-アミノ酸エナンチオマーを得る方法。
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Publication number | Publication date |
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CA2895334A1 (en) | 2014-06-26 |
US20150321994A1 (en) | 2015-11-12 |
KR20150095902A (ko) | 2015-08-21 |
US9688612B2 (en) | 2017-06-27 |
EP2942347A1 (en) | 2015-11-11 |
EP2942347A4 (en) | 2016-08-03 |
EP2942347B1 (en) | 2020-01-22 |
KR102165658B1 (ko) | 2020-10-14 |
CA2895334C (en) | 2020-12-29 |
CN104995175B (zh) | 2018-11-02 |
JP6280506B2 (ja) | 2018-02-14 |
CN104995175A (zh) | 2015-10-21 |
JPWO2014098063A1 (ja) | 2017-01-12 |
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